The influence of zinc status on Akt‐p21 signaling axis in human prostate epithelial cells

Abstract

Previously, we reported that zinc could induce Akt phosphorylation (p-Akt) in prostate cancer LNCaP cells. p-Akt can affect cell cycle progression by phosphorylating p21 and restricting it to the cytoplasm for degradation. With prostate being the highest zinc-accumulating tissue before the onset of cancer, the effect of physiological levels of zinc on human normal prostate epithelial cell (PrEC) and LNCaP cell growth and Akt-p21 signaling axis was examined herein. Cells were cultured for 6 d in low zinc (≤ 0.1 μM) growth medium added with 0 (zinc-deficient; ZD), 4 (zinc-normal; ZN), 16 (zinc-adequate; ZA), or 32 (zinc-supplemented; ZS) μM of zinc. One subgroup of ZD cells (zinc-repleted; ZR) was depleted with ZD for 5 d and then repleted with ZS for 1 d. Cellular zinc status was significantly altered in a dose-dependent manner. For LNCaP cells, p-Akt was higher and cytoplasmic p21 was lower in ZD, ZA, ZS, and ZR than ZN cells. When treated with an Akt inhibitor, LY294002, both levels were depressed. However, zinc had no effect on nuclear p21 protein level and on cell cycle progression. For PrEC, p-Akt was higher in ZD and ZR than ZN cells and these levels were normalized to that of ZN cells by LY294002. Cytoplasmic p21 protein was not affected by zinc. However, nuclear p21 protein was higher in ZA and ZS than ZN cells which coincided with slower G2/M progression. With LY294002, nuclear p21 protein was elevated in all groups, which correlated with an increase in G0/G1 and a decrease in S phases. Hence, zinc may affect cell cycle through Akt-p21 signaling axis differently in normal versus cancerous prostate cells. (USDA NRI)